PO.TB10.19 · 肿瘤生物学
Treg特异性抑制hedgehog信号改变其功能并阻碍小鼠三阴性乳腺癌的生长
Treg-specific inhibition of hedgehog signaling alters their function and impedes the growth of murine triple-negative breast cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
本研究的核心目的是揭示并从机制上阐述Hedgehog（Hh）信号在小鼠三阴性乳腺癌（TNBC）背景下CD4+调节性T细胞（Treg）中的作用。我们采用一种新型基因工程小鼠模型、小鼠TNBC模型、流式细胞术和靶向分子检测，提供了有力证据表明抑制Treg中的Hh活性可减弱其抑制功能，进而减缓肿瘤生长。TNBC是一种侵袭性乳腺癌，治疗选择有限。由于TNBC中Treg丰富，常存在免疫抑制性肿瘤微环境（TME），可能扼杀任何治疗获益。Treg受Foxp3的转录调控，抑制其他肿瘤浸润淋巴细胞和固有免疫细胞，并与较差的患者预后相关。Hh信号通常在胚胎发育、组织再生和干细胞更新中发挥关键作用。重要的是，Hh信号在四分之一的所有癌症中异常上调，而在TNBC中，它与耐药性、肿瘤生长、迁移和侵袭有关。我们实验室近期的工作已证明，系统性药理学抑制Hh信号可导致TNBC的TME中Treg丰度和功能下降。在本研究中，我们报告以Foxp3依赖方式诱导性敲除Hh转录因子Gli2可阻碍乳腺肿瘤生长。由此产生的TME以Treg丰度降低和炎性Th17细胞增加为特征。为揭示这些变化背后的机制，我们利用RNA-seq和染色质免疫沉淀qPCR（ChIP-qPCR）。我们的数据表明，Gli2敲除改变了Treg中的转录调控，使其转向炎性Th17细胞。这些Treg的变化在功能上降低了TNBC的TME的免疫抑制性质，并允许形成炎性TME，从而减少肿瘤生长。总的来说，这些发现引入了一种新的免疫治疗策略，用于在TNBC的TME中靶向和削弱Treg。
查看英文原文 English abstract
The central purpose of this study is to uncover and mechanistically describe the role of Hedgehog (Hh) signaling in CD4+ regulatory T cells (Tregs) in the context of murine triple negative breast cancer (TNBC). We employ a novel genetically engineered mouse model, murine TNBC models, flow cytometry, and targeted molecular assays to provide compelling evidence that inhibiting Hh activity in Tregs mitigates their suppressive function and subsequently slows tumor growth. TNBC is an aggressive form of breast cancer with limited treatment options. Any therapeutic benefits can be stifled by an immunosuppressive tumor microenvironment (TME) often found in TNBC due to an abundance of Tregs. Tregs are under transcriptional control of Foxp3, suppress other tumor-infiltrating lymphocytes and innate immune cells, and are associated with worse patient outcomes.Hh signaling normally plays a key role in embryonic development, tissue regeneration, and stem-cell renewal. Importantly, Hh signaling is aberrantly upregulated in a quarter of all cancers, and in TNBC, it has been implicated in drug resistance, tumor growth, migration, and invasion. Recent work from our lab has demonstrated that systemic pharmacological inhibition of Hh signaling led to a decrease in Treg abundance and function in the TME of TNBC.In this study, we report that inducible ablation of the Hh transcription factor, Gli2 , in a Foxp3-dependent manner, impedes mammary tumor growth. The resultant TME is characterized by decreased abundance of Tregs and an increase in inflammatory Th17s. To uncover the mechanism behind these changes, we utilized RNA-seq and chromatin immunoprecipitation qPCR (ChIP-qPCR). Our data demonstrate that Gli2 ablation alters the transcriptional controls in Tregs leading them to pivot towards inflammatory Th17 cells. These changes in Tregs functionally reduce the immunosuppressive nature of the TME of TNBC and permit an inflammatory TME, thereby reducing tumor growth. Cumulatively, these findings introduce a novel strategy for immunotherapy to target and impair Tregs in the TME of TNBC.
利益披露 Disclosure
I. Miranda, None..
C. Swain, None..
B. J. Metge, None..
L. Shevde, None.